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Tau and alpha-synuclein fibrillization in vitro: lessons from surfactant inducers and small molecule inhibitors

Necula, Mihaela
http://rave.ohiolink.edu/etdc/view?acc_num=osu1089239618

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Biophysics.
Understanding the pathways through which tau and alpha-synuclein fibrillize has important implications for clarifying the pathogenesis of Alzheimer’s and Parkinson’s disease. Studying fibrillization pathways in vitro requires reliable quantitative assays. This work validates electron microscopy and static laser-light scattering as quantitative assays for investigating surfactant-induced tau fibrillization. The data shows that quantitative electron microscopy, which is commonly used to detect morphology, can yield accurate measurements of total filament lengths so long as the total tau concentration is constant. Static laser-light scattering is a solution-based method developed for aggregation reactions, including tau aggregation in the presence of fatty acid inducers. This work shows that this assay is a reliable quantitative assay of surfactant-induced protein fibrillization if corrected for the contribution of micellization. Using in part these assays, the mechanism of action of arachidonic acid as tau and alpha-synuclein fibrillization inducer has been characterized in detail, using recombinant proteins and a series of straight chain detergents. Data shows that alkyl sulfate detergents with a minimum chain length and a negative charge constitute new fibrillization inducers. They act in micellar form to facilitate the formation of tau and alpha-synuclein assembly competent intermediates, therefore accelerating filament nucleation. These data suggest a potential role for intracellular membranes in triggering the formation of tau and alpha-synuclein assembly competent intermediates in vivo. In vivo fibrillization pathways are accompanied by posttranslational modifications. Published data show that glycation and pseudophosphorylation of tau at specific sites increase filament mass relative to wild-type tau and these increases correlate with decreases in critical concentration. Thus, posttranslational modifications may stabilize filaments once they nucleate and thereby enhance their accumulation at low intracellular concentrations. Whatever its mechanism, folding of tau and alpha-synuclein in the fibrillization pathway yields species wich may selectively bind pharmacological agents. Here the properties of a small-molecule inhibitor of tau fibrillization were characterized. N744 selectively inhibited tau assembly by interfering with both filament nucleation and extension. N744 also promoted nonrandom tau disaggregation. These data suggest that tau and potentially alpha-synuclein fibrillization are tractable targets for drug discovery and may yield agents useful for diagnosis and treatment of tauopathic and synucleinopathic neurodegenerations.
Jeff Kuret (Advisor)
251 p.
Biophysics, Medical
Alzheimer&8217; s disease, Parkinson&8217; s disease, tau, alpha-synuclein, fibrillization.

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Citations

  • Necula, M. (2004). Tau and alpha-synuclein fibrillization in vitro: lessons from surfactant inducers and small molecule inhibitors [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1089239618

    APA Style (7th edition)

  • Necula, Mihaela. Tau and alpha-synuclein fibrillization in vitro: lessons from surfactant inducers and small molecule inhibitors. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1089239618.

    MLA Style (8th edition)

  • Necula, Mihaela. "Tau and alpha-synuclein fibrillization in vitro: lessons from surfactant inducers and small molecule inhibitors." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1089239618

    Chicago Manual of Style (17th edition)

osu1089239618
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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.